Pharmaceutical composition of pemetrexed

ABSTRACT

The present invention relates to pharmaceutical composition comprising pemetrexed, a ready to use injection comprising pemetrexed. Liquid composition of pemetrexed comprises head space oxygen less than 5%, dissolved oxygen less than 2ppm and individual impurity level less than 0.2%.

FIELD OF INVENTION

The present invention relates to a pharmaceutical composition comprisingpemetrexed, in the form of ready to use injection. Liquid composition ofpemetrexed comprises head space oxygen less than 5%, dissolved oxygenless than 2 ppm and individual impurity level less than 0.5%.

BACKGROUND OF INVENTION

The present invention relates to pharmaceutical composition ofpemetrexed, in particular, a ready to use injection comprisingpemetrexed. Further, invention relates to a liquid compositioncomprising pemetrexed, antioxidant and pharmaceutically acceptableexcipients.

Pemetrexed disodium is chemically described as L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodiumsalt heptahydrate, represented by the chemical structure of Formula (I).

Pemetrexed is an anti-folate anti-neoplastic agent that exerts itsaction by disrupting folate-dependent metabolic processes essential forcell replication. It is believed to work by inhibiting three enzymesthat are required in purine and pyrimidine biosynthesis-thymidylatesynthase (TS), dihydrofolate reductase (DHFR), and glycinamideribonucleotide formyl transferase (GARFT). Pemetrexed is available inthe market under the brand name ALIMTA®.

U.S. Pat. No. 5,344,932 describes pemetrexed, its related compounds andpharmaceutically acceptable cation and provide that the compoundsclaimed therein can be administered parenterally.

It is disclosed in U.S. Pat. No. 6,686,365 that a simple, isotonicsaline solution of pemetrexed is not pharmaceutically acceptable forcommercial purpose due to degradation of the solution to formunacceptable related substances and they prepared ready to use liquidcomposition of pemetrexed using antioxidant monothioglycerol,L-cysteine, and thioglycolic acid. In the present invention it is nowprepared ready to use, liquid solutions of pemetrexed prepared usingantioxidants along with controlled oxygen exposer. Surprisingly thecomposition disclosed in U.S. '365 was found to be stable only atcontrolled temperature or refrigeration. However, composition of thepresent invention improved to prepare the robust formulation by terminalsterilization process. Now achieved formulation is stable at roomtemperature with adequate shelf life.

DETAILED DESCRIPTION OF INVENTION

Present invention relates to a ready to use, stable liquid compositionof pemetrexed can be stored at room temperature and more acceptable inthe treatment. Further novelty in the present invention is solutions ofpemetrexed prepared using antioxidants along with controlled oxygenexposer. This controlled oxygen is head space oxygen (HSO) less than 5%and dissolved oxygen (OD) less than 2 ppm. Further, liquid compositionof the present invention comprises individual impurity level in thefinal product less than 0.2%. The product is manufactured through asimplified process of solubilisation and a standard/conventionalterminal sterilization by autoclaving/steam sterilization with F₀ value1-30 min

Even after autoclaving the characteristic of the formulation remainstable throughout the shelf life the product at normal room temperaturecondition.

To prove the novelty of the present invention we carried out practicalof four types.

-   -   1. With DO less than 2 ppm+With HSO less than 5%    -   2. With DO less than 2 ppm+With HSO more than 5%    -   3. With DO more than 2 ppm+With HSO less than 5%    -   4. With DO more than 2 ppm+With HSO more than 5%

Here all four formulations are terminally sterilized by steamsterilization with F₀ value 1-30 min and the best result we achievedwhen there is combination of DO less than 2 ppm, HSO less than 5% andterminal sterilization by steam sterilization with F₀ value 1-30 min Theresult below focus more on the achievement of the present invention thatis individual maximum impurity is less than 0.5% and total impurity lessthan 1%.

Results of trials:

DO <2 ppm + DO <2 ppm + HSO <5% HSO >5% Test Spec Initial 50° C./75%/1 M50° C./75%/1 M Maximum 0.18 0.25 Individual Impurity Total NMT 1% 0.420.92 1.4  Impurity DO >2 ppm + DO >2 ppm + HSO <5% HSO >5% Test SpecInitial 50° C./75%/1 M 50° C./75%/1 M Maximum 0.21 0.30 IndividualImpurity Total NMT 1% 0.60 1.10 3.30 Impurity

With combination of DO less than 2 ppm, HSO less than 5% and terminalsterilization one batch continued for stability of 3M and 6M andachieved results are as below:

DO <2 ppm + HSO <5% 40° C./75%/3M 40° C./75%/6M Maximum IndividualImpurity 0.13 0.15 Total Impurity 0.29 0.50

This shows that not only antioxidants but other treatments to theproduct are also playing an important role to stabilize the product.

In the present invention at least antioxidant used includes also otherthan monothioglycerol, L-cysteine and thioglycolic acid, selected fromthe group comprising of acetyl cysteine, butylated hydroxy toluene,butylated hydroxy anisole, DL-tocopherol, sodium metabisulfite, sodiumformaldehyde sulfoxylate, EDTA and its derivatives, methionine, ascorbicacid, citric acid and its pharmaceutically acceptable salt, sodiumsulfite and its derivative and the like.

The formulation of present invention exhibits acceptable stability,retains a pharmaceutically desirable appearance, maintains the desiredenantiomeric stability. Further, the formulation provided herein, issuitable for parental dosage.

The present invention particularly provides a pharmaceutical compositioncomprising:

a) pemetrexed in the range of 5-100 mg/ml

b) at least one antioxidant up to 10 mg/ml wherein antioxidant alsoother than monothioglycerol, L-cysteine and thioglycolic acid, selectedfrom the group comprising of acetyl cysteine, butylated hydroxy toluene,butylated hydroxy anisole, DL-tocopherol, sodium metabisulfite, sodiumformaldehyde sulfoxylate, EDTA and its derivatives, methionine, ascorbicacid, citric acid and its pharmaceutically acceptable salt, sodiumsulfite and its derivative etc.; and

c) a pharmaceutically acceptable excipient

Liquid composition of pemetrexed mentioned above is optionally preparedby using the process of terminal sterilization.

“Pemetrexed” refers to the stable salts, acids and free base formsthereof including free acid, the pharmaceutically acceptable alkalimetal, alkaline earth metal, non-toxic metal, ammonium, and substitutedammonium salts etc. In the present invention preferred salt ofpemetrexed is disodium or dipotassium salt.

“Pharmaceutically acceptable excipient” includes a pharmaceuticallyacceptable carrier, diluents, solution or additive known to the skilledart and suitable for parenteral administration like saline, sodiumchloride, mannitol and the like.

Pharmaceutically acceptable excipients may include osmolarity adjustingagent, stabilizing agent, optionally chelating agent, pH adjustingagent, optionally buffering agent, vehicle, etc.

In present invention osmolarity adjusting agent used may include but notlimited to mannitol, sodium chloride, sucrose, dextrose, or combinationthereof etc. Stabilizing agent used may include but not limited tomannitol, sodium chloride, disodium edetate, D,L-Methionine,diethanolamine, human serum albumin tromethamine and the like.

Chelating agent if used may include but not limited to calcium disodiumethylene diamine tetra acetic acid, disodium ethylene diamine tetraacetic acid, sodium ethylene diamine tetra acetic, acid,diethylenetriaminepenta acetic acid and calteridol and the like.

Buffering agent if used may include but not limited to Phosphate buffer,acetate buffer, glycine buffer and tromethamine buffer and the like.

Osmolarity agent may include but not limited to Sodium chloride,dextrose, mannitol, sodium citrate and the like.

Further, pH adjusting agent may include sodium hydroxide, hydrochloricacid, sodium carbonate, citric acid, tromethamine, potassium hydroxide,sodium citrate etc.

Water for injection, any suitable solvent, etc. was used as a vehicle.

It is generally preferred that the process for preparing the formulationincludes the use of a purge of an inert gas. Such inert gases are forexample, nitrogen, argon, and the like.

The present invention further relates to a novelty that product preparedby our invention can withstand terminal sterilization where head spaceoxygen level less than 5% and dissolved oxygen less than 2 ppm with eachindividual impurity level in the final product less than 0.5%.

Below table represents the composition of present invention.

Sr. No. Ingredient % 1 API 1-10 2 Stabilizing agent 0-10 3 Anti-oxidant0.1-2   4 Osmolarity adjusting agent 0-10 5 pH adjusting agent Q.S. 6Water for injection Q.S. 7 Inert gas Q.S.

Process for preparation of liquid dosage form of pemetrexed used in thepresent invention includes following steps but not limited to:

-   -   1. Prepare bulk solution by adding all excipients and API in        pharmaceutically acceptable water, attain dissolve oxygen level        below 2ppm    -   2. Attain pH between 6-8    -   3. Filter and fill in the vial, attain head space oxygen less        than 5%    -   4. Sterilize the solution by steam sterilization with F₀ value        1-30 min

EXAMPLES

The present invention can be described by way of example only. It is tobe recognized that modifications falling within the scope and spirit ofthe description or claims, which would be obvious to a person skilled inthe art based upon the disclosure herein, are also considered to beincluded within the scope of this disclosure.

Ingredient Example 1 Example 2 Example 3 Example 4 Example 5 Pemetrexed10 mg/ml  10 mg/ml  10 mg/ml  10 mg/ml  10 mg/ml Mannitol 10 mg/ml  10mg/ml  10 mg/ml  10 mg/ml  10 mg/ml Methionine — — 2 mg/ml — —Monothioglycerol 1 mg/ml 1 mg/ml — — NaCl 9 mg/ml 9 mg/ml 9 mg/ml 9mg/ml  9 mg/ml Sodium DiSulfite — — — 1.0 mg/ml   — Disodium EDTA — — —— 0.1-0.25 mg/ml    Ascorbic acid — 2 mg/ml 2 mg/ml — — Inert gas Q.S.Q.S. Q.S. Q.S. Q.S. Water for injection Q.S. Q.S. Q.S. Q.S. Q.S.

For the above mentioned examples pH is between 6 and 8.

In all above mentioned examples an individual impurity lever attained isnot more than 0.5%.

Example 1 Example 2 Example 3 Example 4 Example 5 Maximum 0.54 0.18 0.300.32 0.04 Individual Impurity Total 2.7 0.74 1.2 1.7 0.17 Impurity

One more trial of liquid composition of pemetrexed we have taken usingL-cysteine HCl and other pharmaceutically acceptable excipients usingthe same process of preparation mentioned above wherein pH is maintained7.4. The formulation is stable at room temperature. Maximum individualimpurity level in this formulation is 0.15% and total impurity level inthis formulation is 0.50% at 6M 40° C./75%RH.

1-9. (canceled)
 10. A liquid composition of pemetrexed comprising head space oxygen less than 5% with dissolved oxygen less than 2 parts per million (ppm) and individual impurity level in the final product less than 0.5%.
 11. The liquid composition of pemetrexed of claim 1, wherein said composition comprises 5 to 100 mg/mL of pemetrexed or its pharmaceutically acceptable salts, at least one antioxidant and pharmaceutically acceptable excipients.
 12. The liquid composition of pemetrexed of claim 11, wherein the amount of said antioxidant in said composition is 10 mg/mL or less.
 13. The liquid composition of pemetrexed of claim 11, wherein said antioxidant comprises monothioglycerol, L-cysteine, thioglycolic acid or a combination thereof.
 14. The liquid composition of pemetrexed of claim 11, wherein said antioxidant comprises acetyl cysteine, butylated hydroxy toluene, butylated hydroxy anisole, DL-tocopherol, sodium metabisulfite, sodium formaldehyde sulfoxylate, ethylenediamine-tetraacetic acid (EDTA) or its derivatives, methionine, ascorbic acid, citric acid or its pharmaceutically acceptable salt, sodium sulfite or its derivative, or a combination thereof.
 15. The liquid composition of pemetrexed of claim 10, wherein said composition further comprises a pharmaceutically acceptable excipient.
 16. The liquid composition of pemetrexed of claim 15, wherein said pharmaceutically acceptable excipient comprises an osmolarity adjusting agent, a stabilizing agent, an optionally chelating agent, a pH adjusting agent, an optionally buffering agent, a vehicle, or a combination thereof.
 17. The liquid composition of pemetrexed of claim 10, wherein said composition is optionally prepared using a process of terminal sterilization.
 18. The liquid composition of pemetrexed of claim 17, wherein said terminal sterilization is steam sterilization with F₀ value of from 1 to 30 min.
 19. A process for preparing a liquid composition of pemetrexed comprising: a. preparing a solution of excipients and pemetrexed under conditions to maintain dissolved oxygen level of 2 ppm or less; b. filtering and filling a vial with the solution of step (a) and maintaining head space oxygen of less than 5%; and c. sterilizing said solution of said step (b) by steam sterilization with F₀ value of from 1 to 30 min.
 20. A liquid pharmaceutical composition of comprising: about 10 mg/mL of pemetrexed; head space oxygen of less than 5% with dissolved oxygen of less than 2 ppm; and individual impurity level of less than 0.5%.
 21. The liquid pharmaceutical composition of claim 20 further comprising cysteine as an antioxidant.
 22. The liquid pharmaceutical composition of claim 21, wherein the amount of said cysteine is about 2.5 mg/mL. 